Rilpivirine, chemically 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]pyrimidinyl]amino]benzonitrile and has the structural formula:

Rilpivirine (TMC278) is an investigational new drug, developed by Tibotec, for the treatment of HIV infection. It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency, longer half-life and reduced side-effect profile compared with older NNRTIs.
Polymorphism is defined as “the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules”. Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.
Rilpivirine and its salts can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
Rilpivirine and its hydrochloride salt were disclosed in U.S. Pat. No. 7,125,879.
Process for the preparation of rilpivirine was disclosed in U.S. Pat. No. 7,399,856 ('856 patent). According to the '856 patent, rilpivirine can be prepared by reacting the (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride of formula II with 4-(4-chloropyrimidin-2-ylamino)benzonitrile of formula III-a in the presence of potassium carbonate and acetonitrile under reflux for 69 hours. The synthetic procedure is illustrated in scheme I, below:

Process for the preparation of rilpivirine was disclosed in U.S. Pat. No. 7,705,148 ('148 patent). According to the '148 patent, rilpivirine can be prepared by reacting the 4-[[4-[[4-bromo-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile with acrylonitrile in the presence of palladium acetate, N,N-diethylethanamine and tris(2-methylphenyl)phosphine in acetonitrile.
According to the '148 patent, rilpivirine can be prepared by reacting the compound of formula IV with 4-(4-chloropyrimidin-2-ylamino)benzonitrile formula III-a in the presence of hydrochloric acid and n-propanol to obtain a compound of formula VII, and then the compound was treated with acetonitrile and potassium carbonate under reflux for 69 hours. The synthetic procedure is illustrated in scheme II, below:

U.S. Pat. No. 7,563,922 disclosed a process for the preparation of (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride. According to the patent, (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride can be prepared by reacting the 4-iodo-2,6-dimethyl-benzenamine in N,N-dimethylacetamide with acrylonitrile in the presence of sodium acetate and toluene, and then the solid thus obtained was reacted with hydrochloric acid in 2-propanol in the presence of ethanol and diisopropyl ether.
U.S. Pat. No. 7,956,063 described a polymorphic Form A, Form B, Form C and Form D of rilpivirine hydrochloride.
An unpublished application, IN 1415/CHE/2011 assigned to Hetero Research Foundation discloses a process for the preparation of rilpivirine. According to the application, rilpivirine can be prepared by reacting the 4-(4-chloropyrimidin-2-ylamino)benzonitrile with (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride in the presence of p-toluene sulfonic acid monohydrate and 1,4-dioxane.
It has been found that the rilpivirine produced according to the prior art procedures results in low yields. According to the present invention rilpivirine can be obtained in higher yields than the prior art processes.
We have found that a novel process for the preparation of rilpivirine. The process of the invention ensures that rilpivirine is obtained at faster rate with higher yields.
We have also found that a novel process for the preparation of rilpivirine hydrochloride.
The processes of present invention are simple, eco-friendly, inexpensive, reproducible, robust and is well suited on an industrial scale.
We have also found that a rilpivirine hydrochloride monohydrate.
Thus, one object of the present invention is to provide a novel process for the preparation of rilpivirine.
Another object of the present invention is to provide a novel process for the preparation of rilpivirine hydrochloride.
Another object of the present invention is to provide a rilpivirine hydrochloride monohydrate, process for its preparation and pharmaceutical compositions comprising it.